Biconvex rapidly disintegrating dosage forms

ABSTRACT

A method for preparing solid rapidly disintegrating dosage forms shaped as biconvex tablets having symmetrical top and bottom surfaces and dosage forms obtainable thereby.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of application no.PCT/EP97/03065, filed on Jun. 10, 1997, which application claimspriority from U.S. Ser. No. 60/020,259, filed Jun. 17, 1996.

The present invention relates to a process of preparing solid rapidlydisintegrating dosage forms shaped as a biconvex tablets havingsymmetrical top and bottom surfaces, and to dosage forms obtainablethereby.

Solid rapidly disintegrating dosage forms loaded with a predeterminedquantity of an active ingredient are known from GB-A-1,548,022 (U.S.Pat. No. 4,305,502). These solid dosage forms comprise a porous networkof a matrix material carrying an active ingredient, the matrix materialconsisting of a water-soluble or a water-dispersable carrier material.The solid dosage forms are prepared by freeze-drying or lyophilizationof the solvent from a frozen solution or suspension of the matrixmaterial and the active ingredient.

Various improvements for preparing dosage forms by lyophilization havebeen developed. GB-A-2,111,423 and U.S. Pat. No. 4,371,516 disclose suchmethods of preparing solid dosage forms which are rapidly disintegratedby water and in which a network of matrix material carries apredetermined amount of an active ingredient, particularly apharmaceutical substance. Such dosage forms find many applications,particularly where it is desired to administer, dispense or otherwiseutilise an active ingredient in predetermined unit quantities. Forexample, certain active ingredients which are used in solution orsuspension form, but which are difficult or hazardous to transport orstore in such form, may be converted into a solid form which can beadded by the user to an aqueous medium to produce the desired solutionor dispersion containing a predetermined amount of the activeingredient. Further, the active ingredient may be a reagent which can beadded to a known amount of aqueous liquid to produce a standardisedliquid composition which then can be used, for example, in chemicalanalysis. Further, the active ingredient may be a diagnostic compoundwhich has to be added to a biological sample (e.g. blood, urine) andthus allows one to determine the amount of a particular constituentpresent in the sample. Preferably, however, the active ingredient is adrug substance for human or veterinary use. Rapidly dissolving soliddrug dosage forms are particularly suitable for oral administration.When orally administered they generally disintegrate rapidly in themouth (e.g. within one or two seconds) and thus the dosage form is aparticularly advantageous means for administering drugs to humans andanimals. Such dosage forms can be used as alternatives to conventionaltablets, pills or capsules, particularly for patients—humans and animalsalike—who have difficulty in swallowing these conventional dosage forms.U.S. Pat. No. 4,642,903 teaches a procedure for preparing a freeze-driedfoam dosage form using conventional lyophilization techniques whichresults in rapidly dissolving pharmaceutical dosage forms.

WO-93/23017 addresses a problem intrinsic to conventional lyophilizationmethods, namely the lack of uniform porosity in the lyophilized product.Uniform porosity in a lyophilized product is critical for post-loading aplacebo or unloaded dosage form with an active ingredient. WO-93123017concerns a method of producing a dosage form that will avoid crackingand meltback, has adequate strength, and porosity and exhibits a fastspeed of dissolution.

Other methods for the preparation of solid dosage forms which rapidlydisintegrate in the mouth, namely solid state dissolution techniques aredisclosed in U.S. Pat. No. 5,039,540, U.S. Pat. No. 5,215,756, U.S. Pat.No. 5,330,764. and U.S. Pat. No. 5.298,261.

GB-2,119,246 concerns a process of preparing solid dosage forms usingmolds having a side wall or walls diverging outwardly from the base andmaking an angle of at least 5° at the surface of the composition. Whenlyophilizing under-filled molds of this type, one obtains solid shapedarticles which have a more even thickness and thus are flatter thanarticles obtained from underfilled molds with side walls perpendicularto the base.

Solid dosage forms as provided by the prior art are used to deliverpredetermined amounts of active ingredients. Since the administration ofsuch products is associated with many risks, there is a need to packagethem adequately, e.g. in blister packs, and to bestow an identity onthem.

The packaging of solid rapidly disintegrating dosage forms preparedaccording to prior art methods, especially on a large industrial scale,is associated with a number of particular problems. First, thefriability of such dosage forms seriously constrains the methods bywhich they can be transported and handled. Consequently, any reductionin the friability of solid rapidly disintegrating dosage forms willgreatly enhance their industrial utility by relaxing the productionconstraints. A second problem which directly relates to the shape ofsolid rapidly disintegrating dosage forms prepared according to priorart methods concerns the fact that the top and bottom surfaces of thedosage forms often are not symmetrical. Usually the bottom will be aflat surface more or less perpendicular to the side wall or walls of thedosage form, whereas the top surface may be concave or flat, dependingupon the extent to which the molds are filled. Dosage forms in which topand bottom are distinct have the disadvantage that they may call forprocess steps to orient the dosage forms prior to filling them inblister packs (the process involves detecting each individual form'sorientation, and selecting and reversing those forms that have theundesired orientation).

The present invention provides a single solution to all these problems,consisting of imparting a symmetrical convex top and bottom surface tosolid rapidly disintegrating dosage forms. First, this results in dosageforms with less acute angles between side wall or walls and top orbottom surfaces which reduces the friability of the dosage forms. Thesymmetry further means that there is not any longer a distinctionbetween bottom and top of a dosage form once it is removed from itsmold. The biconvex shape has the further advantage that the dosage formscan easily be arranged to lie on one of their convex surfaces by gentlyshaking them. In addition, they can easily be picked up, either duringproduction and packaging, or later by the patient or the personadministering the dosage form.

The biconvex shape of the solid dosage forms prepared according to thepresent invention also serves to distinguish them from other prior artdosage forms and thus may assist in preventing errors by physicians,pharmacists or by the end-users, the patients in the administration ofmedicines loaded onto biconvex-shaped dosage forms.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an oval (elliptical) mold of 0.5 ml (scale 5:1) viewed fromabove and

FIGS. 2 and 3 show two cross sections of the mold of FIG. 1;

FIG. 4 shows a caplet (oblate) mold of 1.0 ml (scale 5:1) viewed fromabove and

FIGS. 5 and 6 show two cross sections of the mold of FIG. 4;

FIG. 7 shows a square mold with rounded corners of 0.5 ml (scale 5:1)viewed from above and

FIGS. 8 and 9 show two cross sections of said mold, and

FIG. 10 shows the oval mold of FIG. 1 together with the correspondingbiconvex solid dosage form obtainable therein.

FIG. 11 shows a round mold together with the corresponding biconvexsolid dosage form obtainable therein.

The present invention is concerned with a process for the preparation ofa solid rapidly disintegrating dosage form comprising a porous networkof matrix forming materials, which process comprises:

overfilling a mold with a predetermined amount of an aqueous compositioncomprising the matrix forming materials so that a convex meniscus iscreated on top of the mold;

freezing the aqueous composition in the mold; and

removing the solvent from the frozen composition by subjecting it tolyophilization or to solid state dissolution, thus leaving a porousnetwork of matrix forming materials;

characterized in that the shape of the bottom surface of the mold is amirror-image of the shape of the frozen meniscus on the top, themirror-plane being parallel to the plane defined by the rim of the mold,thus yielding a dosage form shaped as a biconvex tablet havingsymmetrical top and bottom surfaces.

The aqueous compositions may be frozen by any conventional coolingprocess. For example, the aqueous compositions may be frozen bydispensing it into preformed molds corresponding to the size and shapeof the desired dosage form and subsequently cooling such molds onrefrigerated shelves or in refrigerated chambers. Alternatively, themolds containing the mixture may be passed through a stream of cold gasor vapor, such as liquid nitrogen in a freezing tunnel. In a preferredmethod of freezing, the composition is passed through a freezing tunnelinto which liquid nitrogen is injected, the liquid nitrogen beingvaporised and the resulting cold gaseous nitrogen being passed over thecomposition. Another method for freezing the aqueous compositions in themolds is to surround the molds in dry ice until the aqueous compositionis frozen.

The best-known process of removing solvents from frozen solutions ordispersions is lyophilization which involves desolvation of the mixtureby sublimation of the solvent under a vacuum. If desired, the frozencompositions may be stored in a cold store before the sublimationprocess is carried out. The sublimation may be carried out in a freezedrier by subjecting the frozen composition in the mold to reducedpressure and, if desired, controlled application of heat to aid thesublimation. The pressure can be below 4 mmHg (533 Pa), e.g. below 0.3mmHg (40 Pa), for example 0.1 to 0.2 mmHg (13.3 to 26.6 Pa) or evenbelow 0.05 mmHg (6.7 Pa). The initial temperature in the freeze driermay be, for example, as high as 60° C. and this temperature can bereduced (e.g. to 40° C.) as the temperature of the frozen compositionincreases. Various methods and improvements are described in thereferences cited at the very beginning of the specification. The frozencompositions also may be removed from the mold prior to lyophilization.

The dosage forms can also be prepared by a solid-state dissolutionmethod of removing solid solvent from frozen samples. In this lessconventional method, one or more matrix forming agents are dissolved ordispersed in a first solvent, frozen and subsequently contacted with asecond solvent at a temperature at or higher than the solidificationpoint of the second solvent and at a temperature at or lower than thesolidification point of the first solvent. The first solvent in thesolidified state is substantially miscible with the second solvent,while the matrix forming agent(s) are substantially insoluble in thesecond solvent. The first solvent is thereby substantially removed fromthe solidified matrix yielding a solid matrix substantially free of thefirst solvent. Typically, the first solvent is water and the secondethanol.

The biconvex dosage forms obtainable by the processes according to thepresent invention can be prepared in a variety of sizes. The volume ofthe mold is conveniently in the range of 300 to 2,000 mm³ (0.3 to 2 ml)and the volume of the dosage form is in the range of 350 to 2,500 mm³(0.35 to 2.5 ml). Preferably, the volume of the mold is in the range of350 to 800 mm³ (0.35 to 0.8 ml) and the volume of the dosage form is inthe range of 450 to 1,000 mm³ (0.45 to 1 ml). In other words, theoverfill or the volume of the convex meniscus above the mold can be upto 30% of the volume of the mold itself. Generally speaking saidoverfill will be in the range of from 20% to about 26% of the volume ofthe mold. Besides the extent of the overfill, the size of the convexmeniscus is constrained by the contact angle between the aqueouscomposition and the material forming the rim of the mold and the surfacetension of the aqueous composition. It is important to note that thelarger the overfill is, the greater the curvature of the convex surfacewill be. This, in turn maximizes both the reduction in friability andthe improvement of the handling properties.

The maximum depth of the mold is conveniently in the range of 3.4 to 6mm; or the maximum thickness of the frozen composition in the mold is inthe range of 5.0 to 8.5 mm. This maximum distance is the distancemeasured along the axis perpendicular to the rim of the mold and runningthrough the upmost point of the meniscus on the top of the mold and thedownmost point on the bottom of the mold. Lower values are generally notpreferred because the resulting dosage forms are so thin that theirstrength is often insufficient, whereas larger values for the thicknessare often undesirable because of the difficulty in effectively removingall solvent from such frozen compositions, especially when usinglyophilization for removing the solvent.

The area of the surface defined by the rim of the mold is typically inthe range of 100 to 500 mm² and has a rounded shape. The rounded shapecontributes to the mechanical strength of the dosage form by reducingits friability. Said rounded shape can be circular, elliptical, oblong,oblate or polygonal, the latter preferably with rounded corners if theinternal angle² 90°.

The mold can be, for example a depression in a metal plate (e.g. analuminium plate). The plate may contain more than one depression, eachdepression being of the size and shape corresponding to the desired sizeof the shaped article. However, the mold may also be a depression in asheet of filmic material. The filmic material may contain more than onedepression. The filmic material may be similar to that employed inconventional blister packs which are used for packaging pharmaceuticaltablets and the like medicament forms. For example, the filmic materialmay be made of thermoplastic material with the depressions formed bythermo-forming. The preferred filmic material is a talc-filledpolypropylene film or a polyvinyl chloride film. Laminates of filmicmaterial such as polyvinyl chloride/polyvinylidene chloride, polyvinylchloride/poly-tetrafluorethylene or polyvinyl chloride/polyvinylidenechloride/polyethylene may also be used.

Where lyophilization is used, it may be advantageous to freeze thematrix material solution in molds that are coated or lined for easyrelease of the frozen material. Preferred molds are thermoformed cupsmade in talc-filled polypropylene sheets, optionally siliconized with alayer of silicone/simethicone baked on the surface(s) which come intocontact with the aqueous composition.

The profile and volume of the bottom of the mold can be determined asdescribed hereunder. A first mold having the desired volume and having aflat bottom (parallel to the rim of the mold) with the desired roundedshape is overfilled to the desired extent with the aqueous solution fromwhich the final dosage form is to be prepared. This is processed to adosage form by freezing and removing the solvent. The volume of themeniscus can be determined by substracting the mold volume from thevolume added to the mold, or alternatively by calculating the volumefrom a number of equations describing the top surface of the meniscus.One such way comprises sectioning the dosage form along one or moresymmetry planes, measuring the cross section where said symmetry planeintersects the top surface of the meniscus and determining the equationdescribing said intersection. As one can safely assume that an ellipseadequately describes such intersections, measurement of the major axisand minor axis readily provides the parameters required for eachequation. The equations of the intersections of the top surface of themeniscus with the various symmetry planes (along which the crosssections were made) can then be used to derive the equation describingthe top surface of the meniscus, and using art-known integrationmethods, the volume of the meniscus can then be calculated. With thethus obtained information one can then proceed to calculate how the moldneeds to be reshaped in order to yield a biconvex symmetrical dosageform. For example, one can calculate to which extent the depth of theoriginal mold needs to be reduced so that the volume of the mold isreduced by the volume of the meniscus, followed by adding the mirrorimage of the top meniscus at the bottom of the mold. This proceduresecures that the convex bottom has both the shape and the volume of themeniscus on the top which will eventually be used. The data obtained inthe calculations are then provided to the manufacturer of the mold sothat the convex shaped mold can be shaped in metal.

The aqueous composition may be in a variety of forms such as a solution,a suspension, a dispersion, an emulsion, or a foam. Persons skilled inthe art will recognize acceptable methods for preparing each of these.Water is preferably employed as the solvent in the composition which isfrozen and desolvated. An additional co-solvent (such as an alcohol) mayalso be used if it is desired to improve the solubility, dispersabilityor wettability of any of the ingredients of the composition.

The dosage form comprises a porous network of matrix forming materialscomprising:

i) a water-soluble, hydratable gel or foam-forming material,

ii) a rigidifying agent for the gel or foam-forming material, andoptionally

iii) one or more amino acids.

Suitable water-soluble, hydratable gel or foam-forming materials includeproteinaceous materials such as gelatin, gelatin A, gelatin B, fluidgelatin, modified fluid gelatin, gelatin derivatives, albumin, soy fiberprotein, wheat and psyllium seed proteins, potato protein, papain;phospholipids such as coacervate egg lecithin, or lecithin; gums such asacacia, guar, agar, locust bean, xanthan and tragacanth gum;polysaccharides such as alginates, polymannuronic acid, chitosan,carrageenans, dextrans, dextrins, maltrins (maltodextrins), pectins,polygalacturonic acid, microcrystalline cellulose, corn syrup solids,konjac flour, rice flour, wheat gluten; synthetic polymers such aspolyvinylpyrrolidone, sodium carboxymethyl-cellulose, sodium starchglycolate, hydroxyethylcellulose; and polypeptide/protein orpolysaccharide complexes such as gelatin-acacia complexes, each singlyor in combination.

Suitable rigidifying agents include monosaccharides, linear and cyclicoligosaccharides and polysaccharides, e.g. mannitol, xylitol, sorbitol,dextrose, fructose, sucrose, lactose, maltose, galactose, trehalose;cyclic sugars such as cyclodextrins e.g. beta-cyclodextrin and2-hydroxypropyl-beta-cyclodextrin; dextran, dextrin; and further includeinorganic substances such as sodium phosphate, sodium chloride,magnesium aluminum silicates, magnesium trisilicate, natural clays, or acombination thereof. The preferred rigidifying agent is mannitol.

Suitable amino acids have from 2 to 12 carbon atoms, e.g. glycine,L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline,L-isoleucine, L-leucine, L-phenylalanine, or a combination thereof.Glycine is the preferred amino acid. Dosage forms containing glycine asone of the matrix forming components have several advantages: quickdissolution and disintegration in aqueous media, pleasant taste andmouthfeel, nutritional value, low caloric content and noncariogenicity.Of particular importance is the fact that these dosage forms can beproduced with minimal cracking or meltback and that they have uniformporosity and adequate strength of handling, i.e. resistance todisintegration or crumbling under normal manufacturing and handlingconditions. These latter properties contribute to the feasibility of thepost-loading processes whereby active ingredients are loaded ontoplacebo or unloaded dosage forms.

Preferred matrix forming agents include pharmaceutical grade gelatins,pectins (non-hydrolyzed, partially hydrolyzed or hydrolyzed), glycineand mannitol. A particularly preferred combination of matrix formingagents comprises gelatin, glycine and mannitol.

The percentages and ratios mentioned in the following paragraphs are allby weight.

The solution or dispersion of materials for preparing the matrix cancontain from 0.1% to 15% by weight of gel or foam forming material, inparticular from 1% to 5% more in particular from 1.2% to 3%. It canfurther contain from 0.5% to 10%, in particular from 0.8% to 2.5% byweight of amino acid and from 0.5% to 10%, in particular from 1% to 4%of rigidifying agent, the remainder being solvent and secondarycomponents as mentioned hereinafter.

The ratios between these materials may vary within certain ranges. Inparticular the weight by weight ratio of the total amount of amino acidsto that of the water-soluble, hydratable gel or foam-forming material isfrom 1:1 to 1:3. A preferred ratio is 1.5: 1. The weight by weight ratioof the amount of the water-soluble, hydratable gel or foam-formingmaterial to that of the rigidifying agent is from 2:1 to 1:2. Apreferred ratio is 1.5:2.

Typically, the weight by weight ratio of the total amount of non-solventcomponents to that of the water in the aqueous composition is in therange of about 1:9 to 1:33, in particular from about 1:13 to 1:30, forexample about 1:20.

Solid rapidly dissolving dosage forms find many applications,particularly where it is desired to administer, dispense or otherwiseutilise an active ingredient in predetermined unit quantities. Theactive ingredient in particular is a drug substance for human ofveterinary use.

The active ingredient used in the solid rapidly dissolving dosage formmay be present in a coated form. For example, it may be present inparticulate form and the particles of the active ingredient may becoated with an appropriate coating agent so as to protect it fromprocess diluents, the aqueous environment of the suspension or of theoral or other mucosal cavity. or other environmental conditions thatwould dissolve or deteriorate said active ingredient. These coatingmaterials may be selected from natural or synthetic polymers that areeither hydrophilic or hydrophobic in nature or other hydrophobicmaterials such a fatty acid, glycerides, triglycerides and mixturesthereof. In this way, the taste of the active or bioactive agent may bemasked, while at the same time permitting the solid dosage form todissolve rapidly upon contact with physio-logical diluents. Examples ofbitter active ingredients that may be coated in accordance with thepresent invention include acetaminophen. ibuprofen, chlorpheniraminemaleate, pseudo-ephedrine, dextromethorphan, cisapride, domperidone,risperidone. Pharmaceutical applications comprise dosage forms havingmucoadhesive properties or designed to deliver a drug at a controlledrate; dosing units designed to deliver drugs in the eye, in vaginal,rectal and other body orifices; solid dosage forms designed to replaceliquid formulations; dry medicated preparations for topical applicationafter resolvation (reconstitution); preparation of medicated units orsheets for topical application; preparation of more palatable dosageforms of drugs that exhibit disagreeable organoleptic properties; dosageforms for oral delivery of drugs to persons who have difficultyswallowing tablets or capsules.

Secondary components such as nutrients, vitamins, other activeingredients, sweeteners, flavouring agents, colouring agents,surfactants, preservatives, antioxidants, viscosity enhancers, minerals,diagnostics, fertilizers and insecticides may also be incorporated inthe formulation of the dosage form.

The solution or suspension of which the dosage forms are made mayfurther contain the secondary components mentioned before. Xanthan gumor polyacrylic acid polymers and salts thereof (also referred to ascarbomers or carboxyvinyl polymers, e.g. Carbopol™) may be added inorder to increase viscosity, or to keep the components of the mixture insuspension.

The present invention also provides biconvex, solid rapidlydisintegrating dosage forms obtainable by any one of the processesdescribed hereinbefore.

The speed with which the biconvex tablet prepared by the inventivemethod dis-integrates is dependent entirely or at least in large part onthe choice of matrix forming agent(s), their concentration and thesolidification/desolvation process conditions. In particular, dosageforms of the size mentioned in the examples described hereinafter, willdissolve or disperse rapidly, for example, in less than about 10 secondsand generally faster e.g. in less than about 5 or even less, e.g. within1 to 2 seconds.

The dosage forms disperse rapidly in water, e.g. in less than 10seconds. The disintegration time of a dosage form is determined to checkwhether it is capable of being disintegrated by water sufficientlyrapidly using a standard tablet disintegration apparatus as described inBritish Pharmacopoeia, 1980, Vol II, Appendix XII A, but with thestandard 2.00 mm wire mesh replaced by stainless steel 40 mesh screen. Asample product is placed in a dry tube held above the surface of thewater. The apparatus is started and the sample immersed in water at 20°C. The sample should disperse on the liquid surface and any solidresidue should pass through the 40 mesh screen within 10 seconds,preferably within 5 and ideally within 1 to 2 seconds.

The invention is illustrated further by the following examples whereinthe active ingredients are pharmaceuticals. It is to be understood thatthe methods according to the present invention and the dosage formsthereby obtainable are applicable to many other types of activeingredients.

Experimental part

A number of essential parameters defining convex molds according to thepresent invention are shown in the following Table 1. The followingparameters are listed

V_(t): volume of the dosage form

S_(c): surface defined by the rim of the mold

H_(c): height of the side wall of the mold which is perpendicular toS_(c)

H_(m): height of the meniscus (also the depth of the convex bottom ofthe mold)

H_(t): total height of the dosage form=Hc+2 Hm

Curve 1 (2): values of the major and minor axes defining the ellipticalcurve which describes the intersection of the top surface of themeniscus with a first (second) intersecting cross section along one ofthe symmetry planes

V_(c): volume of part of the mold given by Sc×Hc

Vm: volume of meniscus or of convex bottom of the mold given by(Vt−Vc)/2

The square tablet is shown in FIG. 7, the oblate tablet in FIG. 4, theoval tablet in FIG. 1 and FIG. 10, and the round tablet in FIG. 11.

TABLE 1 PARAMETER/SHAPE SQUARE TABLET OBLATE TABLET V_(t) =Volume_(total) 500 mm³ 1,000 mm³ S_(c) = Surface_(center) length = 11 mmlength = 20 mm rounded corner r= rounded ends r= 5 mm 1.4 mm area =178.54 mm² area = 119.8 mm² H_(c) = Height_(center) 2.00 mm 2.70 mmH_(m) = Height_(meniscus) 1.80 mm (90%) 2.20 mm (81.5%) H_(t) =Height_(total) 5.60 mm 7.10 mm Curve 1 major = 11 mm major = 20 minminor = 3.6 mm minor = 4.4 mm Curve 2 major = 14.4 mm major = 10 mmminor = 3.6 mm minor = 4.4 mm V_(c) = Volume_(center) 239.6 mm³ (47.9%)482.06 mm³ (48.2%) = S_(c) × H₂ V_(m) = Volume_(meniscus) 130.2 mm³(26%) 258.97 mm³ (25.8%) = (V_(t)-V_(c))/2 PARAMETER/SHAPE OVAL TABLETROUND TABLET V_(t) = Volume_(total) 500 mm³ 1,000 mm³ S_(c) =Surface_(center) length = 17 mm r = 8.4 mm breadth = 9.3 mm area =124.17 mm² area = 221.67 mm² H_(c) = Height_(center) 2.25 mm 2.34 mmH_(m) = Height_(meniscus) 1.75 mm (77.8%) 1.85 mm (79.1%) H_(t) =Height_(total) 5.75 mm 6.53 mm Curve 1 major = 17mm 16.8 mm minor = 3.5mm 3.7 mm Curve 2 major = 9.3 mm 16.8 mm minor = 3.5 mm 3.7 mm V_(c) =Volume_(center) 279.39 mm³ (55.9%) 518.71 mm³ (51.2%) = S_(c) × H₂ V_(m)= Volume_(meniscus) 110.31 mm³ (22.1%) 240.65 mm³ (24.1%) =(V_(t)-V_(c))/2

What is claimed is:
 1. A process for the preparation of a solid rapidlydisintegrating dosage form comprising a porous network of matrix formingmaterials, wherein said matrix forming materials comprise i) awater-soluble, hydratable gel or foam-forming material, ii) arigidifying agent for the gel or foam-forming material and optionallyiii) one or more amino acids and which process comprises: overfilling amold with a predetermined amount of an aqueous composition comprisingthe matrix forming materials so that a convex meniscus is created on topof the mold; freezing the aqueous composition in the mold; and removingthe solvent from the frozen composition by subjecting it tolyophilization or to solid state dissolution, thus leaving a porousnetwork of matrix forming materials; characterized in that the shape ofthe bottom surface of the mold is a mirror-image of the shape of thefrozen meniscus on the top, the mirror-plane being parallel to the planedefined by the rim of the mold, thus yielding a dosage form shaped as abiconvex tablet having symmetrical top and bottom surfaces.
 2. A processaccording to claim 1 wherein the volume of the mold is in the range of300 to 2,000 mm3 (0.3 to 2 ml) and the volume of the dosage form is inthe range of 350 to 2,500 mm3 (0.35 to 2.5 ml).
 3. A process accordingto claim 2 wherein the volume of the mold is in the range of 350 to 800mm3 (0.35 to 0.8 ml) and the volume of the dosage form is in the rangeof 450 to 1,000 mm3 (0.45 to 1 ml).
 4. A process according to claim 1wherein the maximum depth of the mold is in the range of 3.4 to 6 mm; orthe maximum thickness of the frozen composition in the mold is in therange of 5.0 to 8.5 mm.
 5. A process according to claim 1 wherein thearea of the surface defined by the rim of the mold is in the range of100 to 500 mm2 and has a rounded shape.
 6. A process according to claim5 wherein said rounded shape is circular, elliptical, oblong, oblate orpolygonal, the latter with rounded corners if the internal angle² 90°.7. A process according to claim 1 wherein the mold is a depression in asheet of filmic plastic material or in a metal plate.
 8. A processaccording to claim 7 wherein the mold is a thermoformed cup in apolypropylene sheet, the surface of which is optionally siliconized. 9.A process according to claim 1 wherein the aqueous composition is asolution, a suspension, a dispersion, an emulsion, or a foam.
 10. Asheet made of filmic plastic material or of metal for use in the processof claim 1 which comprises a plurality of molds arranged in a regularpattern, characterized in that the shape of the bottom surface of eachmold is a mirror-image of the shape of a predetermined convex meniscuson the top, the mirror-plane being parallel to the plane defined by therim of the mold, the sheet thus being suitable for preparing dosageforms shaped as biconvex tablets having symmetrical top and bottomsurfaces.
 11. process according to claim 1 wherein the gel or foamforming material is selected from the group consisting of gelatin,gelatin A, gelatin B, fluid gelatin, modified fluid gelatin, gelatinderivatives, albumin, soy fiber protein, wheat, psyllium seed proteins,potato protein, papain, coacervate egg lecithin, lecithin, acacia, guar,agar, locust bean, xanthan, tragacanth gum, alginates, polymannuronicacid, chitosan, carrageenans, dextrans, dextrins, maltodextrins,pectins, polygalacturonic acid, microcrystalline cellulose, corn syrupsolids, konjac flour, rice flour, wheat gluten, polyvinylpyrrolidone,sodium carboxymethyl-cellulose, sodium starch glycolate,hydroxyethylcellulose; and gelatin-acacia complexes, each singly or incombination.
 12. A process according to claim 10 wherein the rigidifyingmaterial is selected from the group consisting of a mono-saccharide, alinear or cyclic oligosaccharide, a polysaccharide, an inorganicsubstance, and any combination thereof.
 13. A process according to claim12 wherein the rigidifying material is selected from the groupconsisting of mannitol, xylitol, sorbitol, dextrose, fructose, sucrose,lactose, maltose, galactose, trehalose, beta-cyclodextrin,2-hydroxypropyl-beta-cyclodextrin, dextran, dextrin, sodium phosphate,sodium chloride, a magnesium aluminum silicate, magnesium trisilicate,and a natural clay, or any combination thereof.
 14. A process accordingto claim 1 wherein the amino acid is glycine, L-aspartic acid,L-glutamic acid, L-hydroxyproline, L-isoleucine, L-phenylalanine, or acombination thereof.
 15. A process according to claim 1 wherein thematrix forming materials comprise: i) from 0.1% to 15% (w/w) of awater-soluble, hydratable gel or foam-forming material; ii) from 0.5% to10% (w/w) of a rigidifying agent for the gel or foam-forming material;and optionally; iii) from 0.5% to 10% (w/w) of one or more amino acids.16. A process according to claim 15 wherein the matrix forming materialscomprise: i) from 1.2% to 3% (w/w) of a water-soluble, hydratable gel orfoam-forming material; ii) from 1% to 4% (w/w) of a rigidifying agentfor the gel or foam-forming material, and optionally; iii) from 0.8% to2.5% (w/w) of one or more amino acids.
 17. A process according to claim1 wherein the weight by weight ratio of the total amount of amino acidsto that of the water-soluble, hydratable gel or foam-forming material isfrom 1:1 to 1:3; the weight by weight ratio of the amount of thewater-soluble, hydratable gel or foam-forming material to that of therigidifying agent is from 2:1 to 1:2; and the weight by weight ratio ofthe total amount of non-solvent components to that of the water in theaqueous composition ranges from 1:9 to 1:33.
 18. A process according toclaim 17 wherein the weight by weight ratio of the total amount of aminoacids to that of the water-soluble, hydratable gel or foam-formingmaterial is 1:1.5; the weight by weight ratio of the amount of thewater-soluble, hydratable gel or foam-forming material to that of therigidifying agent is 1.5:2; and the weight by weight ratio of the totalamount of non-solvent components to that of the water in the aqueouscomposition ranges from 1:13 to 1:30.
 19. A process according to claim 1wherein the aqueous composition comprises a drug substance for human orveterinary use as an active ingredient.
 20. A process according to claim19 wherein the aqueous composition further comprises a substanceselected from the group consisting of nutrients, vitamins, other activeingredients, sweeteners, flavouring agents, colouring agents,surfactants, preservatives, antioxidants, viscosity enhancers, minerals,diagnostics, fertilizers and insecticides.
 21. A process according toclaim 19 wherein the drug is cisapride[(±)-cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxy-benzamidemonohydrate].
 22. A process according to claim 1 wherein the matrixmaterial can be disintegrated by water at 20° C. within 10 seconds. 23.A solid rapidly disintegrating dosage form obtainable by the process ofclaim 1.